In a study of collaborative care for depression treatment at the University of Washington Medical School, only 63.5% of the control group – which received “usual” care – rated their quality of care as good to excellent.

Kenneth B. Wells, M.D., of RAND, a Santa Monica, Calif.-based think tank, and the University of California, Los Angeles, Neuropsychiatric Institute, was more emphatic. In reporting the results of the Patient Outcomes Research Team (PORT) on depression in JAMA this past January, Wells et al. (2000) wrote, “Quality of care for depression in managed primary care settings is moderate to poor with resultant poor outcomes.”

Both the University of Washington and PORT studies, however, have shown that enhanced interventions can measurably improve both outcomes and patient satisfaction. These findings may offer new fuel to the managed care debate over costs versus efficacy.

Collaborative Care

In the University of Washington study, a team led by Wayne Katon, M.D., compared the effects of a stepped, collaborative care intervention in a primary care setting with a control group receiving usual care. In most cases, usual care consisted of a prescription for antidepressant medication, two or three visits during the first three months of treatment and the option of referral to a mental health program.

Intervention patients were provided with a book and videotape prepared by the study team. These tools reviewed the biology of depression, depression’s relationship to stress, how medications and psychotherapy help depression, and how patients and their significant others could be active partners with their physician in caring for their depressive illness. In addition, patients with severe psychosocial stressors were encouraged to seek psychotherapy or were referred to community-based support groups.

A psychiatrist worked with all of the intervention patients’ primary care physicians to optimize medication usage and to find alternatives if side effects developed. The psychiatrist also monitored the patients’ adherence to the medication regimen through the use of automated pharmacy records and alerted the primary care physician if it appeared the patient had discontinued using the drugs.

Patients in the intervention group were significantly more likely to adhere to the medication regimen than were patients in the control group. At the end of three months, 78.6% of the intervention patients and 62.1% of the control patients had adhered to the medication schedule; at six months, 73.2% of the intervention group versus 50.5% of the control group were still following the medication schedule. Pharmacy records indicated that 68.8% of the intervention patients versus 43.8% of the usual care group received antidepressant medication (at or above the lowest recommended dosage) for at least 90 days.

Response to treatment was based on a Structured Clinical Interview for DSM-IV finding of 0 or 1 of the nine major depressive symptoms at three and six months. At three months, 40% of the intervention patients versus 23% of the usual care patients were asymptomatic (p=0.01); at six months, 44% versus 31% were asymptomatic (p=0.05).

Katon et al. concluded, “The cost per case successfully treated was lower for collaborative care than for usual care because the success rate of treatment was increased more than the total costs of treatment per case.”

Katon also assisted the PORT team, lead author Wells told Mental Health Economics. “Wayne helped on the medication arm of our study. A lot of what we did was learn from what he’s learned about how to support primary care practices and how to package and disseminate the tools without exerting a lot control.”

The PORT Depression Study

The PORT study tested the use of evidence-based materials including training guides, slides, brochures and videos for clinicians, nurse specialists, psychotherapists and patients. Researchers compared the results of quality improvement (QI) programs with usual care at 46 primary care clinics in six managed care organizations.

The research team studied two variant QI programs: one with enhanced resources for supporting medication management (QI-meds) and the other with enhanced resources for providing psychotherapy for depression (QI-therapy). The common elements for each variant included: 1) institutional commitment on the part of the health plan; 2) training of local leaders, including a primary care clinician, a nursing supervisor and a mental health specialist, in each clinical setting; 3) training for local staff; and 4) patient identification.

In QI-therapy, local psychotherapists were trained to provide manualized individual and group therapy for 10 to 16 sessions. In QI-meds, nurse specialists were trained to provide follow-up assessments and support adherence through monthly contacts with the patients for six or 12 months.

At the end of six months, 50.9% of the QI patients and 39.7% of the controls had counseling or used antidepressant medication at an appropriate dosage; at 12 months, 59.2% of the QI patients versus 50.1% (p=0.006) of the controls had done so.

The QI patients showed a markedly greater rate of improvement than the controls. At six months, only 39.9% of the QI patients still met the criteria for probable depressive disorder, compared with 49.9% of the control group (p=0.001). QI patients were 8% to 10% less likely to have probable disorder at six and 12 months; in addition, QI patients showed a 5% increase in employment retention.

“To our knowledge,” the team wrote, “no QI study has demonstrated improved employment, although perceived interpersonal work functioning improves with efficacious treatment for major depression.”

Wells told Mental Health Economics the PORT study showed “when practices that are not academically based make a modest effort to do the right thing and organize their resources to support doctors’ and patients’ decisions, the patients will benefit over a long period of time”

Patient Presentation and History

JS is a 37-year-old female who comes to the pharmacy intending to purchase St. John’s wort. She has heard that it can relieve depression, and she firmly believes in “natural” treatments. She reports that, for the past three weeks, she has been feeling depressed, has had a decreased appetite with a 15-pound weight loss, has had little energy, no longer enjoys the many recreational activities that pleased her in the past, and finds herself waking up each morning three hours earlier than expected with an inability to fall back to sleep. She is unable to identify any significant, recent stressors in her life, but says that it is becoming increasingly difficult to perform adequately at work and home. She had her annual, routine physical exam one month ago, and all physical and laboratory findings were within normal limits. Aside from her current complaints, she has been in good physical health with no medical problems, alcohol or substance abuse, allergies, or regular use of prescription or nonprescription drugs.

St. John’s Wort

Botanical and Chemical Properties: St. John’s wort (Hypericum perforatum L.), belonging to the family Hypericaceae and also known as klamath weed, amber touch-and-heal, goatweed and rosin rose, is an aromatic shrubby perennial plant with numerous bright yellow flowers that bloom from June to September. The blooms are said to be at their brightest and most abundant around the day traditionally celebrated as the birthday of John the Baptist (June 24).

The plant is native to Europe and can be found as well in the United States and Canada. It is an aggressive weed found in the dry ground of roadsides, meadows, woods and hedges, where it generally grows to a height of one to two feet. Historically, St. John’s wort has been used as an herbal remedy, not only for depression, but also to treat anxiety, diuresis, gastritis and insomnia. In addition, it has been investigated as a treatment for cancer and AIDS.

Low concentrations of hypericin and pseudohypericin are found in the leaves and flowers of St. John’s wort. Other active ingredients are flavonoids, xanthones, phenolic carboxylic acids, essential oils, carotenoids, alkanes, phloroglucinol derivatives, phytosterols, and medium-chain fatty acid alcohols. Tannin, in a concentration of approximately 10%, is most likely responsible for St. John’s wort’s astringent and protein-precipitating effects, contributing to the plant’s traditional, topical use as a wound-healing agent.

Pharmacology

Historically, people thought that the tranquilizing effects of St. John’s wort were secondary to increased capillary blood flow. More recent studies demonstrate that the extract, primarily hypericin, is a strong, and nearly irreversible, inhibitor of monoamine oxidase types A and B. In addition, the extract enhances sleep, extends narcotic-induced sleeping time in a dose-dependent manner, antagonizes the effects of reserpine and decreases aggressive behavior in socially isolated male mice. The Food and Drug Administration has designated hypericin as an investigational new drug. In Germany, it has been approved by the regulatory authorities for the treatment of depression.

Clinical Trials

Hypericum has been tested in over 3,000 patients against placebo and various active medications.2 Linde et al. conducted a meta-analysis of 23 randomized trials (15 in which hypericum was compared with placebo and 8 in which it was compared with another drug treatment); 1,757 outpatients with mainly mild or moderately severe depressive disorders were included. Overall, results of this analysis indicated that extracts of hypericum are more effective than placebo and equal in efficacy compared to standard antidepressants for the treatment of mild to moderately severe depressive disorders. In addition, fewer side effects were seen in patients treated with hypericum (19.8%) than in those treated with standard antidepressants (52.8%).

In a four-week, double-blind trial of 105 outpatients with mild depression of short duration, 67% of patients taking hypericum extract (300 mg three times daily) improved, compared with 28% of patients taking placebo. No significant side effects were noted.

In two studies, hypericum was compared with a standard heterocyclic antidepressant. In one, lasting six weeks, the dose of hypericum extract was 300 mg three times daily and that of imipramine was 25 mg three times daily. Hamilton Depression Rating Scale scores decreased from 20.2 to 8.8 in the hypericum group and from 19.4 to 10.7 in the imipramine group. In addition, fewer and milder side effects were noted in the patients treated with hypericum than in those treated with imipramine. In the other study, lasting four weeks, hypericum extract was compared with maprotiline in 102 depressed patients. The dose of hypericum extract was 300 mg three times daily and that of maprotiline was 25 mg three times daily. At the end of the study, no significant differences in either group were noticed. Overall, the relatively low doses of imipramine and maprotiline and short treatment periods make the results of these studies difficult to interpret.

No trials have been published comparing hypericum with any of the selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine), nor has there been systematic investigation of its efficacy over the long-term (i.e., six or more months) treatment period required for a major depressive episode. In addition, it has not been studied in patients with severe depression.

Adverse Effects and Toxicity

No adverse effects (e.g., changes in EEG, ECG, or laboratory test parameters) have been reported following treatment for up to six weeks with a standardized hypericum extract in controlled human studies. However, St. John’s wort has been associated with severe photosensitivity in animals grazing extensively on the plant. Photosensitization in humans is characterized by inflammation of the skin and mucous membranes following exposure to light. Toxicity in humans seems unlikely if the agent is used at recommended medicinal doses. Although not reported, orthostatic hypotension is theoretically possible in light of the drug’s monoamine oxidase-inhibiting properties.

Drug Interactions

Although no systematic studies of drug interactions have been conducted, patients taking St. John’s wort should observe the same precautions followed by those taking monoamine oxidase inhibitors (e.g., phenelzine and tranylcypromine). Foods containing large amounts of tyramine (e.g., aged meats and cheeses) and sympathomimetic amines (e.g., amphetamine, phenylpropanolamine, and pseudoephedrine) should be avoided in order to minimize any risk of a hypertensive crisis. In addition, serotonergic agents (e.g., selective serotonin reuptake inhibi-tors, such as venlafaxine, nefazodone, mirtazapine and buspirone, as well as trazodone, some tricyclic antidepressants, lithium, meperidine and possibly dextromethorphan) should be avoided to minimize the risk of a serotonin syndrome, a potentially life-threatening excess in serotonergic activity characterized by confusion, agitation, shivering, fever, diaphoresis, diarrhea, myoclonus, hyperreflexia and tremor.

Dosage

When used for its antidepressant action, St. John’s wort has generally been used as an extract, standardized to contain 0.3% hypericin, taken in a dosage of 300 mg three times daily. Significant effectiveness may not be seen for several weeks, and two or three months of continuous use may be needed to achieve a full effect.

Conclusion

St. John’s wort, in the form of an extract, seems to offer an intriguing option for the treatment of depression, especially in patients with mild to moderately severe depression who insist upon “natural” treatments. In short-term trials, it appears to be effective and, at the same time, relatively safe and well tolerated. However, the potential risks associated with its monoamine oxidase inhibiting activity and ability to induce photosensitivity require a degree of caution. Further studies are needed to assess the role of St. John’s wort in the treatment of severe depression, its long-term efficacy and side effects, as well as to compare it with full therapeutic doses of heterocyclic and newer antidepressants.

Pharmacist Intervention

The symptoms described by JS are classic for a major depression; there does not appear to be a medical or psychosocial etiology. Her preference for a “natural” remedy and her moderate depression make her a good candidate for St. John’s wort. However, the pharmacist must inform the patient of the limitations in our current knowledge regarding this treatment, as well as the significant morbidity and mortality associated with inadequately treated depression. The relative risks and benefits of both standard antidepressants and St. John’s wort should be reviewed. Since JS is of child-bearing age, she must be informed of our lack of information regarding possible teratogenic effects of St. John’s wort.

If JS still wishes to try this “natural” alternative, the pharmacist should become involved in monitoring the therapeutic response and any emergent side effects, as well as advising her to avoid certain foods and drugs and to protect herself against photosensitivity while using St. John’s wort. Finally, the patient should be referred back to her primary care provider or to a local institution or clinic that specializes in the evaluation and treatment of depressive disorders, especially if she does not show a positive response within a few weeks of use. Patient counseling and monitoring, of course, should also be provided to all other patients who wish to try this and other herbal medicines.